ABSTRACT (PROJECT 3) Project 3 focuses on the pleiotropic damage response known as cellular senescence. The senescence response is an essentially permanent arrest of cell proliferation, accompanied by phenotypic changes, including the development of a senescence-associated secretory phenotype (SASP). The SASP entails the robust expression and secretion of a suite of pro-inflammatory cytokines, chemokines, growth factors and proteases. We have now firmly established that the SASP is a response to genomic/epigenomic damage, and that it can profoundly alter tissue microenvironments and promote both degenerative and hyperplastic phenotypes associated with aging. In this renewal application, we will use human and mouse cell cultures and mouse models to critically determine the role of cellular senescence in damage-induced aging phenotypes, and more thoroughly explore the costs and benefits of the senescence response in the context of aging. We will also determine the role of longevity mediators that have been and will be studied within the PPG in modulating various senescent cell phenotypes. Our specific aims are designed to answer the following questions: To what extent and under which circumstances do senescent cells contribute to aging phenotypes? To what extent do the longevity-associated genes studied in the PPG alter the phenotype(s) of senescent cells? And to what extent and under what circumstances do senescent cells benefit the organism, specifically by promoting wound healing? Our proposed experiments will provide a critical analysis of the extent to which senescent cells drive aging phenotypes, important information on how senescent phenotypes are regulated, and insights into novel benefits of the senescence response. In addition to generating important basic knowledge, the experiments will also provide a framework for developing and understanding potential interventions into aging phenotypes.